Technical Field
This disclosure relates to methods for detecting and scoring expression of Programmed Death Ligand-1 (PD-L1) in tumor tissues, particularly in conjunction with therapies that disrupt signaling initiated by PD-L1.
Brief Description of Related Art
Human PD-L1 encodes a 290 amino acid (aa) type I membrane precursor protein with a putative 18 aa signal peptide, a 221 aa extracellular domain, a 21 aa transmembrane region, and a 31 aa cytoplasmic domain. Human PD-L1 is constitutively expressed in several organs such as heart, skeletal muscle, placenta and lung, and in lower amounts in thymus, spleen, kidney and liver. PD-L1 expression is upregulated in a small fraction of activated T and B cells and a much larger fraction of activated monocytes. PD-L1 expression is also induced in dendritic cells and keratinocytes after IFN gamma stimulation.
PD-L1 is involved in the negative regulation of some immune responses and may play an important role in the regulation of peripheral tolerance. PD-L1 is known to bind to two receptors: Programmed cell death protein 1 (PD-1, also known as PCDP-1 and CD279); and B7-1 (also known as CD80). Interaction of PD-L1 with PD1 or with B7-1 results in inhibition of TCR-mediated proliferation and cytokine production (Freeman et al., J. Exp. Med. 192(7): 1027-34 (2000); Butte et al., Immunity 27(1): 111-22 (2007)). PD-L1 has been suggested to play a role in tumor immunity by increasing apoptosis of antigen-specific T-cell clones (Dong et al. Nat Med 8:793-800 (2002)). Indeed, PD-L1 expression has been found in several murine and human cancers, including human lung, ovarian and colon carcinoma and various myelomas (Iwai et al. PNAS 99:12293-7 (2002); Ohigashi et al. Clin Cancer Res 11:2947-53 (2005)). Thus, measuring the amount of PD-L1 protein in biological samples may aid in the early detection of cancer pathologies and may help assess the efficacy and durability of investigational drugs that inhibit the binding of the PD-L1 protein.